We have identified two inbred mouse strains, C57BL/6J (B6) and C3H/HeJ (C3H), that differ by 40% in serum IGF-I levels. Furthermore, this difference in serum IGF-I (B6=low; C3H=high) is accompanied by a marked difference of 50% in femoral bone mineral density (BMD; B6 = low, C3H = high) and in skeletal IGF-I content. Preliminary data on F2 progeny of genetic crosses between these two strains show that serum IGF-I levels co- segregate with high or low BMD and that IGF-I accounts for nearly 40% of the variance in BMD. The distribution of serum IGF-I levels in these F2 progeny demonstrates that IGF-I is a polygenic trait that can be analyzed by quantitative trait loci (QTL) methodology. To assess the functional effects of IGF-1 on bone mass in the absence of GH regulation, we have developed C3H and B6 strains carrying the mutant gene little (lit) that result in genetic deficiency in serum GH. Preliminary data show that despite genetic GH deficiency, serum IGF-1 and BMD are significantly higher in the C3H-lit/lit compared with the B6-lit/lit. Therefore, genes in the C3H/HeJ background other than GH are exerting detectable influence on serum IGF-1 and on BMD. In this application we will test two hypothesis: 1) Serum IGF-I is a polygenic trait whose genetic components can be mapped, and 2) IGF-1 is a major determinant of bone mass in mice, acquisition and maintenance of bone mass. The two specific aims of this proposal are: 1) To map the heritable factors that control serum IGF-1 levels by utilizing QTL methodology to locate chromosomal regions with molecular markers that co-segregate with high and low serum IGF-1 in F2 progeny and in specific congenic strains of lit/lit mice; and, 2) To assess the functional relationship between IGF-1 and bone mass by measuring BMD by pQCT, bone mineral content by pDEXA, biochemical markers, and histomorphometry in F2 progeny and congenic strains of mice. From these studies, we will demonstrate that IGF-I is critical factor for the acquisition and maintenance of bone mass. In addition, we will define specific foci in addition to GH that regulate the IGF-I phenotype. These results should have wide spread implications for both understanding and treating disorders of low bone mass.